Genomic Variations in the Structural Proteins of SARS-CoV-2 and Their Deleterious Impact on Pathogenesis: A Comparative Genomics Approach

Abstract

A continual rise in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease (COVID-19) has become a global threat. The main problem comes when SARS-CoV-2 gets mutated with the rising infection and becomes more lethal for humankind than ever. Mutations in the structural proteins of SARS-CoV-2, i.e., the spike surface glycoprotein (S), envelope (E), membrane (M) and nucleocapsid (N), and replication machinery enzymes, i.e., main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) creating more complexities towards pathogenesis and the available COVID-19 therapeutic strategies. This study analyzes how a minimal variation in these enzymes, especially in S protein at the genomic/proteomic level, affects pathogenesis. The structural variations are discussed in light of the failure of small molecule development in COVID-19 therapeutic strategies. We have performed in-depth sequence- and structure-based analyses of these proteins to get deeper insights into the mechanism of pathogenesis, structure-function relationships, and development of modern therapeutic approaches. Structural and functional consequences of the selected mutations on these proteins and their association with SARS-CoV-2 virulency and human health are discussed in detail in the light of our comparative genomics analysis.

SARS-CoV-2 Mutations and Their Impact on Diagnostics, Therapeutics and Vaccines

“…Fitness-enhancing mutations have been reported in nsp3, namely F206F, S1197R and T1198K, that has been associated with increased severity of infection for B.1.1 lineages ( 52 ). Further, certain mutations in 3CLpro: T45I, K90R, R279C, A266V, A234Vand N151D have been found in the VOCs B.1.1.7, B.1.351, P.1 and B1.617 ( 58 ). Mohammad et al ( 58 ) further speculate T190I and A191V in 3CLpro can alter polarity and affect the binding of therapeutic molecules.…”

“…Further, certain mutations in 3CLpro: T45I, K90R, R279C, A266V, A234Vand N151D have been found in the VOCs B.1.1.7, B.1.351, P.1 and B1.617 ( 58 ). Mohammad et al ( 58 ) further speculate T190I and A191V in 3CLpro can alter polarity and affect the binding of therapeutic molecules. Moreover, several geographical studies have been published, where Indian samples reveal a high mutation frequency in nsp2, nsp3, nsp4, nsp5, nsp6, nsp12, nsp14, and nsp16 ( 59 ).…”

Investigating host-virus interaction mechanism and phylogenetic analysis of viral proteins involved in the pathogenesis

“…The recent outbreak of the COVID-19 pandemic from Wuhan province of China has shackled the world, causing severe damage to the world population and economy, which is still persistent and threatening the nations despite the fast development of various vaccines claiming to be up to >90% efficacy against the virus [ 92 – 94 ]. Human coronavirus has been linked to mild to severe respiratory tract infections in humans.…”

“…The genome of the human coronavirus is made up of ssRNA that encodes various structural and non-structural genes. Envelope protein (E), membrane protein (M), and spike protein (S) embedded in lipid bilayers aid the virus in host entry and assimilation [ 94 ]. S protein is responsible for virus binding and cell entry into a host body.…”

Impact of Single Amino Acid Substitutions in Parkinsonism-Associated Deglycase-PARK7 and Their Association with Parkinson’s Disease

“…PARK7 acts as both a causative and carcinogenic gene and plays a crucial role in oxidative stress [10]. Because mutations in PARK7 cause various complex diseases, we studied several variants of PARK7 using state-of-the-art computational approaches [12][13][14][15][16]. We took 152 mutations of the whole protein to explore their consequences in disease progression.…”